Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

作者：Kinoshita Manao; Hirayama Yuri; Fujishita Kayoko; Shibata Keisuke; Shinozaki Youichi; Shigetomi Eiji; Takeda Akiko; Ha Pham Ngoc Le; Hayashi Hideaki; Hiasa Miki; Moriyama Yoshinori; Ikenaka Kazuhiro; Tanaka Kenji F; Koizumi Schuichi^*

来源：EBioMedicine, 2018, 32: 72-83.

DOI：10.1016/j.ebiom.2018.05.036

• Astrocytes
• Fluoxetine
• ATP
• Adenosine
• Vesicular nucleotide transporter
• BDNF

Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyteselective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyteselective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y11 and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission.

• 出版日期2018-6